4 suggesting that CMYA3 is directly regulated by Ang II signaling. This gene, since named Xirp2 (also known as mXin␤ and myomaxin), is a direct target of the MEF2A transcription factor and is markedly downregulated in hearts lacking MEF2A. 5,6 Xirp2 belongs to the ancient, muscle-specific, actin-binding Xin gene family whose expression can be traced to ancestral vertebrates with a 2-chambered heart. 7-9 Xirp2 is expressed in cardiac and skeletal muscle where it interacts with filamentous actin and ␣-actinin through the novel actin-binding motif, the Xin repeat. 5,8 In striated muscle, Xirp2 localizes to the peripheral Z-disc region, or costamere, 5 and the intercalated disk. 10,11 The subcellular localization of Xirp2 is significant in that the costamere and intercalated disk harbor mechanical stress sensors that are critical for normal muscle function. [12][13][14] Antisense knockdown of Xin in developing chick embryos, the sole Xin family member in this species, results in a severe disruption of cardiac looping morphogenesis. 9 In mice, a lossof-function mutation of mXin␣, the mammalian ortholog of Xin, results in cardiomyopathy and conduction defects. 11 In the present study we sought to determine the role of Xirp2 in cardiac development and/or function. Mice harboring a hypomorphic Xirp2 allele are viable but display cardiac hypertrophy. As Xirp2 is regulated by Ang II, we also examined cardiac pathology in hypomorphic mice with long-term administration of this hormone. In contrast to wild type mice exposed to a chronic Ang II infusion, hypomorphic mice displayed diminished cardiac hypertrophy, fibrosis, and apoptosis. Furthermore, we demonstrate that regulation of Xirp2 gene expression in response to Ang II signaling is mediated by MEF2A. Our results suggest that Original

Background The angiotensin II (AngII) type 1 receptor (AT1) regulates cardiovascular function by activating various signal pathways. The purpose of this study was to evaluate the effects of a mutant AT1 receptor on AngII responding blood pressure and cardiac hypertrophy in conjunction with altered AngII activation of RhoA and Akt. Methods A mutant AT1 receptor was constructed and overexpressed in FVB mice using a ubiquitous-expression vector pCAGGS. The phenotype and signal transduction of the transgenic mice were compared with the wild type (WT) mice. Results The transgenic mice showed a similar baseline phenotype as WT mice, but their blood pressure in response to continuous AngII infusion was significantly lower, as measured on day 3, 4, 7 and 14, with a difference of 20 mmHg by day 14. There was also a significantly larger heart to total body weight ratio in the WT mice, whose heart weight was 0.441 ± 0.008 % of total body weight compared to the transgenic mice at 0.416 ± 0.008 %. Aortic endothelial cells isolated from these transgenic mice displayed an altered signaling profile, such as diminished activation of Akt and RhoA in response to AngII. In contrast, Gαq coupling and ERK/JNK activation did not change. Conclusion The expression of an AT1 mutant receptor in the presence of WT receptor can effectively modulate AngII effected signaling. Furthermore, the elimination of Akt and RhoA activation by AngII significantly reduces but does not eliminate its hypertensive effect.

We have therefore documented that overexpression of the alpha(2B)-AR gene leads to increased production of alpha(2B)-AR protein in brain regions known to regulate central sympathetic outflow, thus resulting in sustained BP elevation. This is a unique model of experimental hypertension driven purely by overexpression of the alpha(2B)-AR that would result in an overactive sympathetic system and would be suitable for testing the pharmacologic properties of potential therapeutic agents.

Background Diagnosing D‐Dimer early is essential to optimize clinical treatment and quality of life and reduce mortality. This study aims to identify the difference of D‐Dimer levels (ng/ml) in patients with stroke within the 6‐ and 24‐h period compared to patients that mimic stroke. Methods An electronic database search across PubMed/MEDLINE, Cochrane, Web of Science, CINAHL, EMBASE, and Scopus was conducted until December 10, 2021. Studies were eligible if they included adult patients with stroke compared to stroke mimics or controls reporting D‐Dimer values. Quality assessment was conducted using GRADE. The standardized mean difference and 95% confidence intervals were calculated in addition to the difference of means in the crude form. Heterogeneity was assessed using Cochran's Q statistic and the I2 index. A random‐effects model was used. The statistical analysis was conducted using RevMan 5.4. Results Out of 2901, there were 318 (11%) participants from upper‐middle‐income countries, whereas the others were from high‐income countries. Large positive effect size was found for D‐Dimer in the stroke group (Cohen's d = 2.82 [1.73–3.9]; p < 0.00001), meaning that those with stroke had higher D‐Dimer values on presentation compared to the stroke mimics/controls. A large difference in means was found in the two groups (MD = 685.1 [324.2, 1045.99]; p < 0.00001), suggesting that there was a significantly higher laboratory value in the stroke group. Conclusion Our findings must be used in caution as the most reliable diagnostic tests for stroke are CT and MRI. Laboratory testing such as D‐Dimer values is a valuable clinical adjuvant in diagnosing total stroke.

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